Cancer is characterized by the inappropriate growth or survival of a malignant cell compared to its normal counterpart. Under physiologic conditions, the survival, proliferation, and differentiation of cells is controlled by growth factors, cytokines, and hormones. It is not surprising that the intracellular pathways activated by these factors, which promote the physiologic growth and survival of cells, can be subverted in cancer as a result of the underlying mutations in a tumor cell.
Although cytokines and hormones can trigger the activation of a number of intracellular signaling pathways, it is becoming increasingly clear that members of the Stat family of transcription factors are key mediators of their effects (Darnell J E, Jr. Science 1997; 277:1630-1635; Ihle J N. Cell 1996; 84:331-334). For example, Stats have been found to function inappropriately in many human malignancies (Alvarez J V, Febbo P G, Ramaswamy S, Loda M, Richardson A, Frank D A. Cancer Res 2005; 65(12):5054-62; Frank D A. Cancer Treat. Res. 2003; 115:267-291; Bowman T, et al. Oncogene 2000; 19(21):2474-88). Further, compounds which inhibit Stat3 activity inhibit the proliferation of breast cancer cells (Song et al., PNAS; 20(13); 4700-4705 (2005)).
However, compounds which activate Stat3 may also have beneficial effects. For example, activated Stat3 was shown to protect tissue from ischemic injury and heart failure (Hilfiker-Kleiner et al., Cir. Res. 95:187-195 (2004); Stephanou, J. Cell. Mol. Med., 8(4):519-525 (2004)). Furthermore, Stat3 activation increases self-renewal and in-vitro proliferation of stem cells (U.S. Publication No. 2003/0157711, filed Feb. 18, 2003).